{"gene":"PRPF31","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2002,"finding":"PRPF31 (61K protein) is required for U4/U6·U5 tri-snRNP formation and subsequent spliceosome assembly and pre-mRNA splicing. Immunodepletion of 61K from HeLa nuclear extracts inhibits tri-snRNP formation; complementation with recombinant 61K restores all steps. 61K is operationally U4/U6 snRNP-specific but also interacts with the U5 snRNP-associated 102K protein (PRPF6), physically tethering U4/U6 to U5 to yield the tri-snRNP.","method":"Immunodepletion from HeLa nuclear extracts, recombinant protein complementation, two-hybrid analysis, biochemical co-sedimentation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with immunodepletion and complementation, plus two-hybrid and biochemical validation; multiple orthogonal methods in single rigorous study","pmids":["11867543"],"is_preprint":false},{"year":2007,"finding":"The conserved Nop domain of hPrp31 is a genuine RNP-binding module that recognizes a composite RNA-protein platform consisting of the 15.5K protein bound to U4 snRNA. The Nop domain exhibits both RNA and protein binding surfaces, and binding specificity is maintained despite relaxed RNA sequence requirements. Yeast two-hybrid analyses linked RP-causing mutations to an aberrant hPrp31–hPrp6 interaction that blocks U4/U6·U5 tri-snRNP formation.","method":"Crystal structure analysis of hPrp31–15.5K–U4 snRNA complex, biochemical binding assays, yeast two-hybrid","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation and mutagenesis; multiple orthogonal methods in single rigorous study","pmids":["17412961"],"is_preprint":false},{"year":2004,"finding":"RNAi knockdown of hPrp31 (61K) in HeLa cells inhibits tri-snRNP formation in vivo, causing accumulation of stable U4/U6 di-snRNPs and U5 mono-snRNPs. In the absence of hPrp31, U4/U6 di-snRNPs and the recycling factor p110 accumulate in Cajal bodies, while U5 snRNPs remain in nucleoplasmic speckles, supporting a role for Cajal bodies in tri-snRNP recycling.","method":"RNAi in HeLa cells, biochemical fractionation, fluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with defined cellular and biochemical phenotype plus direct fluorescence localization; two orthogonal methods; replicated conceptually with parallel hPrp6 knockdown","pmids":["15257298"],"is_preprint":false},{"year":2006,"finding":"hPrp31 binding to U4 snRNP requires the kink-turn structure (stem I and two-base-pair stem II) of the U4 5'-stem-loop pre-bound with 15.5K protein. Stem I could not be shortened and introduction of a third Watson-Crick base pair into stem II significantly reduced hPrp31 binding. The two-base-pair stem II of U4/U4atac snRNAs discriminates hPrp31 binding from NOP56/NOP58 binding to box C/D snoRNAs (which require a three-base-pair stem II).","method":"Hydroxyl radical footprinting, electrophoretic mobility shift assay (EMSA) with systematic U4 snRNA mutants, in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis and footprinting; single lab but multiple orthogonal biochemical methods","pmids":["16857676"],"is_preprint":false},{"year":2011,"finding":"Crystal structure analysis shows that the capping pentaloops of U4 and U4atac 5'-stem-loops adopt different conformations in ternary hPrp31–15.5K–snRNA complexes. In U4atac snRNA, a noncanonical base pair forms across the pentaloop enabling more intimate contacts with hPrp31; stacking of hPrp31-His270 on this base pair stabilizes the complex. Rational mutagenesis confirmed these interactions, explaining how hPrp31 achieves dual specificity for both U4 and U4atac snRNAs.","method":"Crystal structure analysis, gel-shift assays, rational mutagenesis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis and binding assays; single lab but multiple orthogonal methods","pmids":["21784869"],"is_preprint":false},{"year":2002,"finding":"Two RP11-linked missense mutations (A194E and A216P) in PRPF31 substantially hinder translocation of the protein into the nucleus when expressed in mammalian cells, as shown by western analysis and immunofluorescence. The A216P mutation introduced into yeast PRP31p only partially rescues growth at the restrictive temperature, indicating incomplete splicing function. No dominant-negative effect on splicing was detected in a human cell in vivo splicing assay.","method":"Yeast complementation assay, in vivo splicing assay in human cells, western blot, immunofluorescence microscopy","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (yeast complementation, human splicing assay, immunofluorescence) in single study; single lab","pmids":["12444105"],"is_preprint":false},{"year":2005,"finding":"Mutant PRPF31 proteins significantly inhibit pre-mRNA splicing of rhodopsin (RHO) intron 3 in retinal cells, as demonstrated by immunoprecipitation of PRPF31-containing splicing complexes that co-purify RHO transcripts. Expression of mutant PRPF31 in primary retinal cultures reduces rhodopsin expression and causes apoptosis of rhodopsin-positive retinal cells.","method":"Immunoprecipitation of splicing complexes, minigene splicing assay, primary retinal cell culture with mutant PRPF31 expression, immunofluorescence","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complexes plus functional splicing assay and primary cell apoptosis readout; single lab, multiple methods","pmids":["15659613"],"is_preprint":false},{"year":2007,"finding":"Immunoprecipitation-coupled microarray analysis identified peripherin/RDS and FSCN2 transcripts as being associated with PRPF31-containing splicing complexes in retinal cells. Minigene assays demonstrated that mutant PRPF31 significantly inhibits pre-mRNA splicing of RDS and FSCN2, linking ubiquitous splicing factor dysfunction to photoreceptor-specific gene expression defects.","method":"Immunoprecipitation-coupled microarray (IP-chip), minigene splicing assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with follow-up functional minigene validation; single lab, two orthogonal methods","pmids":["17350276"],"is_preprint":false},{"year":2008,"finding":"Most PRPF31 mutations introducing premature termination codons result in null alleles through nonsense-mediated mRNA decay (NMD). Allele-specific measurement confirmed strong reduction of mutant transcripts; blocking NMD restored mutant mRNA but did not restore truncated protein synthesis even with proteasome inhibitors, indicating the pathogenic mechanism is haploinsufficiency rather than dominant-negative gain-of-function.","method":"Allele-specific RT-PCR, NMD inhibition, western blot, protein degradation pathway inhibitors","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal molecular methods (allele-specific qRT-PCR, NMD inhibition, western blot with proteasome inhibitors) across 9 patient cell lines; multiple PRPF31 mutations tested","pmids":["18317597"],"is_preprint":false},{"year":2006,"finding":"PRPF31 is imported into the nucleus via interaction with importin beta1, with no requirement for importin alpha1, as shown by GST pull-down assays. The disease-linked mutations A194E and A216P do not affect this importin beta1 interaction. FRAP of EGFP-tagged PRPF31 revealed a two-component nuclear entry process (fast tau ~6 s, slow tau ~80 s), unchanged by the mutations.","method":"GST pull-down with importin proteins, fluorescence recovery after photobleaching (FRAP) in live cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical pulldown plus live-cell FRAP; single lab, two orthogonal methods","pmids":["16427773"],"is_preprint":false},{"year":2008,"finding":"The A216P (AD29) missense mutation in hPrp31 destabilizes the protein structure, leading to rapid degradation and significantly reduced association with U4 and U5 snRNPs in the cell nucleus. Overexpression of hPrp6 (a binding partner) reverses the effects of AD29 on cell proliferation and Cajal body structure. The mutation's pathology involves both insufficiency of functional hPrp31 and potential cytotoxicity from the unstable mutant.","method":"Co-immunoprecipitation with snRNPs, protein stability assays, cell proliferation assay, fluorescence microscopy of Cajal bodies, hPrp6 rescue overexpression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and cellular assays (Co-IP, stability, rescue by hPrp6); single lab","pmids":["19293337"],"is_preprint":false},{"year":2008,"finding":"The A216P mutation in PRPF31 directly reduces splicing efficiency of RHO minigene intron 3 in an in vivo mammalian cell assay, and pull-down assays show that the mutant PRPF31 has a stronger interaction with PRPF6 than wild-type, suggesting a mechanism for splicing inhibition. Splicing of full-length RHO transcript is 100% efficient, indicating RP11 missense mutations act mainly through protein insufficiency/insolubility with a minor direct splicing effect.","method":"In vivo minigene splicing assay in transfected mammalian cells, GST pull-down assay between PRPF31 and PRPF6","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assay plus protein interaction pulldown; single lab, two orthogonal methods","pmids":["18431455"],"is_preprint":false},{"year":2011,"finding":"CTNNBL1, an armadillo-motif nuclear protein, interacts with PRPF31 through the nuclear localization sequence (NLS) of PRPF31. CTNNBL1 binds NLSs via its ARM domain, exhibiting selectivity distinct from karyopherin-alpha, suggesting a possible role in selective intranuclear targeting or interactions of splicing-associated complexes.","method":"Co-immunoprecipitation, pulldown assays, identification of NLS-binding specificity","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and pulldown; single lab but multiple binding assays demonstrating specific NLS-dependent interaction","pmids":["21385873"],"is_preprint":false},{"year":2012,"finding":"CNOT3, a subunit of the Ccr4-NOT transcription complex, acts as a transcriptional repressor of PRPF31. siRNA-mediated silencing of CNOT3 increases PRPF31 expression; chromatin immunoprecipitation showed CNOT3 directly binds the PRPF31 promoter. CNOT3 is the major modifier gene determining penetrance of PRPF31 mutations, and its variable expression correlates inversely with PRPF31 levels.","method":"siRNA knockdown of CNOT3, chromatin immunoprecipitation (ChIP), quantitative RT-PCR, western blot, next-generation sequencing of CNOT3 genomic region","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional siRNA rescue, and mRNA/protein correlation; multiple orthogonal methods; independent replication of PRPF31 expression-penetrance correlation","pmids":["23144630"],"is_preprint":false},{"year":2017,"finding":"PRP31 is ubiquitinated with K63-linked chains by the PRP19 complex and deubiquitinated by USP15 together with its substrate-targeting factor SART3. The USP15-SART3 complex also forms a ternary complex with USP4 to deubiquitinate PRP3. The ubiquitination/deubiquitination status of PRP31 regulates its interaction with U5 snRNP component PRP8, which is required for efficient splicing of chromosome-segregation genes, likely by stabilizing the U4/U6·U5 tri-snRNP complex.","method":"Co-immunoprecipitation, ubiquitin linkage analysis, siRNA knockdown, in vitro splicing assays, mass spectrometry","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitin linkage typing, functional rescue assays, and splicing readout; multiple orthogonal methods in single study","pmids":["28088760"],"is_preprint":false},{"year":2018,"finding":"Prp31 and Sf3A2 directly bind spindle microtubules and the Ndc80 kinetochore complex in both Drosophila and human cells, with the Ndc80/HEC1-SF interaction restricted to M phase. Antibody injection into Drosophila embryos disrupts mitotic division within 1 minute, demonstrating a direct (non-splicing-mediated) role in chromosome segregation. In cells depleted of Prp31, the Ndc80 complex is not tightly associated with kinetochores.","method":"Anti-Prp31 antibody microinjection into Drosophila embryos, RNAi depletion in HeLa cells, co-immunoprecipitation with Ndc80 complex, microtubule binding assays, immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody injection with <1 min mitotic effect (rules out splicing mechanism), Co-IP with Ndc80, localization studies; multiple orthogonal methods in both fly and human cells","pmids":["30475206"],"is_preprint":false},{"year":2018,"finding":"In PRPF31-mutated patient-derived retinal organoids and RPE cells, disrupted alternative splicing occurs for specific splicing programs including genes encoding pre-mRNA splicing proteins and genes implicated in ciliogenesis and cellular adhesion. RPE defects include disrupted apical-basal polarity, reduced trans-epithelial resistance, reduced phagocytic capacity, and decreased cilia length and incidence. In situ CRISPR/Cas9 correction of the pathogenic mutation rescued protein expression and key cellular phenotypes.","method":"Patient iPSC-derived retinal organoids and RPE, transcriptome profiling, Prpf31+/- mouse retina analysis, CRISPR/Cas9 correction with phenotypic rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptomics plus multiple cellular functional assays plus genetic rescue (CRISPR); corroborated in Prpf31+/- mouse model","pmids":["30315276"],"is_preprint":false},{"year":2019,"finding":"Mutant PRPF31 protein forms cytoplasmic aggregates in the RPE of a Prpf31-A216P mouse model, reducing nuclear protein levels. Wild-type PRPF31 is recruited into insoluble aggregates when mutant protein is overexpressed in vitro. In response to aggregation, Hspa4l (HSP70 family member) is overexpressed, which may facilitate correct folding and nuclear translocation of mutant protein.","method":"Mouse model analysis (Prpf31-A216P/+), immunofluorescence, protein solubility fractionation, in vitro overexpression, western blot","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus in vitro biochemistry showing aggregate recruitment and chaperone response; single lab","pmids":["31892304"],"is_preprint":false},{"year":2021,"finding":"In prpf31 knockout zebrafish, retinal progenitor cell (RPC) differentiation and viability are severely disrupted at early embryonic stages. Mitotic arrest and DNA damage occur specifically in RPCs. Prpf31 deletion predominantly causes skipping of exons with weak 5' splice sites. Differentially spliced genes are enriched for DNA repair and mitotic progression functions. Wild-type human PRPF31 but not disease-associated mutants rescues the zebrafish phenotype.","method":"prpf31 knockout zebrafish, transcriptome-wide splicing analysis, cell cycle and DNA damage assays, human PRPF31 rescue expression","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined cellular phenotype, transcriptome-wide splicing analysis, and genetically validated rescue with WT vs mutant human PRPF31","pmids":["33476374"],"is_preprint":false},{"year":2022,"finding":"In PRPF31-mutated patient iPSC-derived RPE and retinal organoid cells, mutant PRPF31 is not incorporated into splicing complexes. Reduced PRPF31 wild-type levels cause tri-snRNP assembly defects in Cajal bodies, altered nuclear speckle morphology, and reduced active spliceosome formation. Progressive cytoplasmic aggregates containing mutant PRPF31 and ubiquitin-conjugated proteins accumulate. Activation of autophagy with rapamycin reduces cytoplasmic aggregates and improves cell survival.","method":"iPSC-derived RPE and retinal organoids, quantitative proteomics, immunofluorescence of Cajal bodies/nuclear speckles, spliceosome assembly assays, rapamycin treatment","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus cellular organelle analysis and pharmacological rescue; single lab but multiple orthogonal approaches","pmids":["35297555"],"is_preprint":false},{"year":2019,"finding":"PRPF31 reduction causes mis-splicing of phototransduction genes (RHO, ROM1, FSCN2, GNAT2, GNAT1) and RNA processing genes (PRPF3, PRPF8, PRPF4, PRPF19) in human organotypic retinal cultures. The splicing defects were identified by RNA-seq analysis of differential exon usage and intron retention after RNAi-mediated knockdown of PRPF31.","method":"RNAi knockdown in human organotypic retinal cultures, RNA-seq with differential exon usage and intron retention analysis","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with genome-wide splicing readout in tissue-relevant model; single lab","pmids":["31654038"],"is_preprint":false},{"year":2016,"finding":"PRPF31 is involved in HBV covalently closed circular DNA (cccDNA) production. PRPF31 knockdown by siRNA decreased cccDNA formation, and expression of siRNA-resistant PRPF31 rescued cccDNA formation. Chromatin immunoprecipitation and co-immunoprecipitation revealed association between PRPF31 and cccDNA, and co-overexpression of PRPF31 and HBx enhanced cccDNA formation.","method":"siRNA knockdown, rescue overexpression, chromatin immunoprecipitation, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with rescue, ChIP, and Co-IP; single lab, multiple methods but non-retinal function","pmids":["27864147"],"is_preprint":false},{"year":2022,"finding":"PRPF31 interacts with PRPH2 (peripherin-2) as shown by co-immunoprecipitation and co-localization in HEK293T, ARPE-19 cells, and mouse retina. PRPF31 could be pulled down with an anti-PRPH2 antibody.","method":"Co-immunoprecipitation, immunofluorescence co-localization","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and co-localization; single lab, limited functional follow-up","pmids":["36088804"],"is_preprint":false},{"year":2023,"finding":"The USH1G protein SANS directly binds PRPF31 via two distinct conserved regions of its CENTn domain, as shown by FRET assays and in silico structural predictions. Pathogenic USH1G/SANS variants perturb binding to PRPF31 and PRPF6, and a conformational change in an intrinsically disordered region of SANS CENTn2 to a short alpha-helix is triggered by PRPF6 binding, suggesting sequential interactions.","method":"Fluorescence resonance energy transfer (FRET) in cells, deep learning-based protein structure prediction, domain mapping","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — FRET in cells plus in silico predictions; no reconstitution or structural validation; single lab","pmids":["38139438"],"is_preprint":false},{"year":2025,"finding":"PRPF31 deficiency in 661W photoreceptor-like cells downregulates FSCN2 expression and reduces cilia number (as measured by IFT88 and ARL13B markers). RNA immunoprecipitation showed PRPF31-FSCN2 interaction. Overexpression of FSCN2 partially rescued the ciliary defects caused by PRPF31 knockdown, identifying a PRPF31–FSCN2 regulatory axis for photoreceptor ciliogenesis.","method":"RNAi knockdown, RNA immunoprecipitation (RIP), FSCN2 rescue overexpression, cilia quantification, RT-qPCR, western blot","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrating interaction, functional RNAi with rescue; single lab, multiple methods","pmids":["41265626"],"is_preprint":false},{"year":2024,"finding":"PRPF31 deficiency in zebrafish causes severe defects in hematopoietic stem and progenitor cell (HSPC) expansion. Prpf31-deficient HSPCs undergo malformed mitosis and M-phase arrest during expansion. Transcriptome analysis revealed extensive perturbation of alternative splicing of mitosis-related genes, mechanistically linking PRPF31 splicing function to HSPC proliferation.","method":"prpf31 knockout zebrafish, immunofluorescence, transcriptome/splicing analysis, flow cytometry of hematopoietic lineages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with cellular phenotype and transcriptome-wide splicing validation; single lab","pmids":["38382674"],"is_preprint":false},{"year":1996,"finding":"Yeast Prp31p (ortholog of human PRPF31) is essential for cell viability and required for pre-mRNA splicing both in vivo and in vitro, as shown by temperature-sensitive mutant analysis and direct splicing assays. The wild-type PRP31 gene was cloned by complementation; epitope-tagged Prp31p is functional in vivo.","method":"Temperature-sensitive mutant characterization, in vivo and in vitro splicing assays, gene cloning by complementation, western blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro splicing assay plus in vivo complementation; foundational yeast study establishing essential splicing function","pmids":["8604353"],"is_preprint":false},{"year":2000,"finding":"Fission yeast prp31+ is essential for vegetative growth and meiotic progression, and is synthetically lethal with prp6. Temperature-sensitive prp31-E1 cells display a pre-mRNA splicing defect at the restrictive temperature, confirming Prp31 as a general splicing factor required in both mitotic and meiotic contexts.","method":"Temperature-sensitive mutant, synthetic lethality with prp6, in vivo splicing analysis, gene cloning by complementation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (synthetic lethality with prp6) plus direct splicing assay; single study in fission yeast ortholog","pmids":["10871341"],"is_preprint":false},{"year":2026,"finding":"PRPF31 deficiency downregulates polo-like kinase 4 (PLK4), relieving its inhibition of transcription factor EB (TFEB). This triggers TFEB nuclear translocation and transcriptional upregulation of autophagy/lysosomal genes, driving autophagic hyperactivation. The resulting autophagic hyperactivation causes mitochondrial dysfunction (structural abnormalities, respiratory deficits, ATP deficiency, ROS accumulation), establishing a PLK4-TFEB-autophagy-mitochondria pathogenic axis.","method":"Multi-model approach (cell lines, animal models), protein localization, autophagy assays, mitochondrial function assays, transcriptional reporter assays","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-model mechanistic pathway dissection with functional readouts; single lab, newly published","pmids":["41932639"],"is_preprint":false}],"current_model":"PRPF31 encodes a ubiquitously expressed spliceosomal protein whose Nop domain binds a composite RNP platform (15.5K protein + U4/U4atac snRNA kink-turn) and also contacts PRPF6 (hPrp6/102K), physically tethering the U4/U6 di-snRNP to the U5 snRNP to form the U4/U6·U5 tri-snRNP required for each round of pre-mRNA splicing; K63-linked ubiquitination of PRPF31 by the PRP19 complex (reversed by USP15-SART3) regulates its interaction with PRPF8, controlling tri-snRNP dynamics; in the absence of PRPF31, U4/U6 di-snRNPs accumulate in Cajal bodies implicating these organelles in tri-snRNP recycling; PRPF31 additionally binds spindle microtubules and the Ndc80 kinetochore complex to directly support chromosome segregation independently of splicing; and in photoreceptors/RPE, haploinsufficiency caused by NMD-mediated destruction of mutant alleles leads to mis-splicing of phototransduction and ciliogenesis genes, RPE ciliary defects, progressive cytoplasmic protein aggregation, and a PLK4-TFEB-autophagy-mitochondria stress cascade, collectively causing the retina-restricted degeneration of RP11."},"narrative":{"mechanistic_narrative":"PRPF31 is an essential pre-mRNA splicing factor that drives assembly of the U4/U6·U5 tri-snRNP required for each round of splicing [PMID:11867543, PMID:8604353]. Its conserved Nop domain recognizes a composite RNP platform—the 15.5K protein bound to the kink-turn of the U4 (and U4atac) snRNA 5'-stem-loop—and the geometry of a two-base-pair stem II discriminates this binding from box C/D snoRNP proteins, allowing PRPF31 to engage both U4 and U4atac snRNAs [PMID:17412961, PMID:16857676, PMID:21784869]. By simultaneously contacting this U4/U6-associated platform and the U5 snRNP protein PRPF6, PRPF31 physically tethers the U4/U6 di-snRNP to U5 to generate the tri-snRNP; loss of PRPF31 blocks tri-snRNP formation and causes U4/U6 di-snRNPs and the recycling factor p110 to accumulate in Cajal bodies, implicating these bodies in tri-snRNP recycling [PMID:11867543, PMID:15257298]. K63-linked ubiquitination of PRPF31 by the PRP19 complex, reversed by USP15-SART3, modulates its interaction with PRPF8 and thereby tunes tri-snRNP dynamics and splicing of chromosome-segregation genes [PMID:28088760]. Beyond splicing, PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during M phase to support chromosome segregation, a function independent of its splicing role [PMID:30475206]; consistent with this, PRPF31 loss causes mitotic arrest and DNA damage in proliferating progenitor populations [PMID:33476374, PMID:38382674]. Mutations in PRPF31 cause autosomal dominant retinitis pigmentosa (RP11) through haploinsufficiency: premature-termination alleles are eliminated by nonsense-mediated decay and missense alleles such as A216P destabilize and mislocalize the protein, with disease penetrance set by the transcriptional repressor CNOT3 acting on the PRPF31 promoter [PMID:18317597, PMID:19293337, PMID:23144630]. Reduced PRPF31 dosage produces retina-specific pathology—mis-splicing of phototransduction and ciliogenesis genes, RPE ciliary and polarity defects, cytoplasmic protein aggregation, and a PLK4-TFEB-autophagy-mitochondria stress cascade [PMID:30315276, PMID:31654038, PMID:41932639].","teleology":[{"year":1996,"claim":"Established that the PRPF31 ortholog is an essential, conserved general splicing factor, setting the functional baseline for the human protein.","evidence":"Temperature-sensitive mutants and in vivo/in vitro splicing assays in budding yeast Prp31p, with cloning by complementation","pmids":["8604353"],"confidence":"High","gaps":["Did not define the snRNP step at which Prp31p acts","Human protein not yet characterized"]},{"year":2000,"claim":"Genetic epistasis showed Prp31 functions together with Prp6, foreshadowing the di-snRNP–U5 bridging role.","evidence":"Temperature-sensitive prp31 mutant and synthetic lethality with prp6 in fission yeast, plus splicing analysis","pmids":["10871341"],"confidence":"Medium","gaps":["Mechanism of the Prp31–Prp6 functional interaction not defined","Did not test the human orthologs directly"]},{"year":2002,"claim":"Defined the specific molecular step PRPF31 controls—tri-snRNP formation—by showing depletion blocks assembly and recombinant protein restores it, and identified PRPF6 as its U5 contact.","evidence":"Immunodepletion/complementation of HeLa nuclear extracts, two-hybrid, and co-sedimentation","pmids":["11867543"],"confidence":"High","gaps":["Structural basis of RNP and PRPF6 binding not yet resolved","In vivo consequence of loss not addressed"]},{"year":2002,"claim":"First connected RP-causing missense mutations to a cellular defect, showing impaired nuclear import and incomplete splicing function without dominant-negative splicing inhibition.","evidence":"Yeast complementation, human in vivo splicing assay, immunofluorescence and western blot of A194E/A216P","pmids":["12444105"],"confidence":"Medium","gaps":["Did not resolve whether pathology is haploinsufficiency or toxicity","Import defect mechanism unexplained"]},{"year":2004,"claim":"Demonstrated in vivo that PRPF31 loss arrests tri-snRNP assembly and traps U4/U6 di-snRNPs in Cajal bodies, implicating these bodies in tri-snRNP recycling.","evidence":"RNAi in HeLa cells with biochemical fractionation and fluorescence microscopy","pmids":["15257298"],"confidence":"High","gaps":["Did not define how Cajal-body localization couples to recycling","Recovery kinetics of the tri-snRNP not measured"]},{"year":2006,"claim":"Defined the RNA determinant of PRPF31 binding—the U4 kink-turn with a two-base-pair stem II—explaining specificity against snoRNP proteins.","evidence":"Hydroxyl-radical footprinting and EMSA with systematic U4 snRNA mutants","pmids":["16857676"],"confidence":"High","gaps":["Did not resolve atomic contacts (later by crystallography)","Protein-binding surface not mapped here"]},{"year":2006,"claim":"Identified importin beta1 as the nuclear-import receptor for PRPF31 and showed RP mutations do not impair this interaction, narrowing the basis of mutant mislocalization.","evidence":"GST pull-down with importins and FRAP of EGFP-PRPF31 in live cells","pmids":["16427773"],"confidence":"Medium","gaps":["Reconciliation with earlier reported import defect of mutants unresolved","Two-component entry kinetics not mechanistically explained"]},{"year":2007,"claim":"Provided the structural mechanism: the Nop domain is a bona fide RNP-binding module recognizing the 15.5K–U4 platform, and RP mutations act by perturbing the PRPF31–PRPF6 interaction that builds the tri-snRNP.","evidence":"Crystal structure of hPrp31–15.5K–U4 snRNA with binding assays and yeast two-hybrid","pmids":["17412961"],"confidence":"High","gaps":["Did not capture the full tri-snRNP assembly intermediate","Functional consequence in retina not tested"]},{"year":2005,"claim":"Linked PRPF31 dysfunction to photoreceptor biology by showing mutant protein impairs splicing of retinal transcripts and triggers apoptosis of rhodopsin-positive cells.","evidence":"Immunoprecipitation of splicing complexes, minigene assays, and primary retinal cultures with mutant PRPF31","pmids":["15659613"],"confidence":"Medium","gaps":["Did not separate direct splicing inhibition from protein insufficiency","Mechanism of retina specificity unaddressed"]},{"year":2007,"claim":"Extended the retinal target set, identifying RDS/peripherin and FSCN2 transcripts whose splicing is sensitive to mutant PRPF31.","evidence":"IP-coupled microarray and minigene splicing assays in retinal cells","pmids":["17350276"],"confidence":"Medium","gaps":["Direct binding versus complex co-purification not distinguished","Quantitative dosage dependence not established"]},{"year":2008,"claim":"Resolved the disease mechanism as haploinsufficiency by showing PTC alleles are degraded by NMD with no rescued truncated protein, excluding dominant-negative gain-of-function.","evidence":"Allele-specific RT-PCR, NMD and proteasome inhibition, western blot across patient cell lines","pmids":["18317597"],"confidence":"High","gaps":["Did not explain why only the retina degenerates","Missense alleles handled in separate studies"]},{"year":2008,"claim":"Showed the A216P missense allele destabilizes the protein, reduces snRNP association, and is rescued by excess PRPF6, supporting an insufficiency mechanism for missense mutations.","evidence":"Co-IP with snRNPs, stability and proliferation assays, Cajal-body imaging, hPrp6 overexpression rescue","pmids":["19293337"],"confidence":"Medium","gaps":["Relative contribution of insufficiency versus mutant cytotoxicity not quantified","Single lab"]},{"year":2008,"claim":"Showed that A216P paradoxically binds PRPF6 more tightly while reducing minigene splicing, refining the view that RP11 missense mutations act mainly through insufficiency/insolubility.","evidence":"In vivo minigene splicing assay and GST pull-down between PRPF31 and PRPF6","pmids":["18431455"],"confidence":"Medium","gaps":["Stronger PRPF6 binding not mechanistically reconciled with reduced function","Effect on full tri-snRNP not measured"]},{"year":2011,"claim":"Resolved the dual snRNA specificity by showing distinct pentaloop conformations of U4 versus U4atac and a His270 stacking contact stabilizing the complex.","evidence":"Crystal structures of ternary hPrp31–15.5K–snRNA complexes with gel-shift and rational mutagenesis","pmids":["21784869"],"confidence":"High","gaps":["Functional consequence for minor-spliceosome splicing not tested in cells"]},{"year":2011,"claim":"Identified CTNNBL1 as an NLS-binding partner with selectivity distinct from karyopherin-alpha, hinting at a dedicated intranuclear targeting route.","evidence":"Co-IP and pulldown mapping NLS-dependent binding","pmids":["21385873"],"confidence":"Medium","gaps":["Functional role of the interaction not established","No in vivo validation"]},{"year":2012,"claim":"Explained variable penetrance of PRPF31 mutations by identifying CNOT3 as a direct transcriptional repressor whose expression sets residual wild-type PRPF31 dosage.","evidence":"siRNA knockdown, ChIP at the PRPF31 promoter, qRT-PCR/western, and sequencing of CNOT3","pmids":["23144630"],"confidence":"High","gaps":["Did not identify the trans/cis variants controlling CNOT3 levels in patients","Tissue-specific regulation not addressed"]},{"year":2016,"claim":"Implicated PRPF31 in HBV cccDNA formation, indicating a function beyond the spliceosome.","evidence":"siRNA knockdown with rescue, ChIP, and Co-IP linking PRPF31 to cccDNA and HBx","pmids":["27864147"],"confidence":"Medium","gaps":["Direct versus indirect role in cccDNA biogenesis not resolved","No structural basis for cccDNA association"]},{"year":2017,"claim":"Revealed a regulatory layer: K63-ubiquitination of PRPF31 by the PRP19 complex, reversed by USP15-SART3, controls PRPF31–PRPF8 interaction and splicing of chromosome-segregation genes.","evidence":"Reciprocal Co-IP, ubiquitin-linkage typing, siRNA, in vitro splicing, and mass spectrometry","pmids":["28088760"],"confidence":"High","gaps":["Ubiquitination site(s) on PRPF31 not mapped","How modification status is signaled remains unknown"]},{"year":2018,"claim":"Established a splicing-independent, direct mitotic function: PRPF31 binds spindle microtubules and the Ndc80 complex during M phase, with rapid antibody-injection effects ruling out a splicing mechanism.","evidence":"Antibody microinjection in Drosophila embryos, HeLa RNAi, Co-IP with Ndc80, microtubule-binding and imaging","pmids":["30475206"],"confidence":"High","gaps":["Structural basis of microtubule/Ndc80 binding unresolved","Relationship to splicing pool of PRPF31 not defined"]},{"year":2018,"claim":"Modeled RP11 in human retinal organoids/RPE, showing disrupted splicing of splicing and ciliogenesis genes plus RPE polarity, barrier, phagocytosis, and ciliary defects, with CRISPR correction rescuing phenotypes.","evidence":"Patient iPSC-derived retinal organoids and RPE, transcriptomics, Prpf31+/- mouse retina, CRISPR/Cas9 correction","pmids":["30315276"],"confidence":"High","gaps":["Causal chain from mis-splicing to ciliary defect not fully traced","Retina-restriction still unexplained"]},{"year":2019,"claim":"Defined the retinal mis-splicing program upon PRPF31 reduction, including phototransduction and RNA-processing genes.","evidence":"RNAi in human organotypic retinal cultures with RNA-seq for differential exon usage and intron retention","pmids":["31654038"],"confidence":"Medium","gaps":["Which mis-spliced events are causal for degeneration not isolated","Single model system"]},{"year":2019,"claim":"Identified protein aggregation as a downstream consequence, showing mutant PRPF31 forms cytoplasmic aggregates that sequester wild-type protein and induce an HSP70 chaperone response.","evidence":"Prpf31-A216P mouse RPE, solubility fractionation, in vitro overexpression, and western blot","pmids":["31892304"],"confidence":"Medium","gaps":["Whether aggregation is cause or consequence of degeneration unclear","Hspa4l rescue not functionally tested in vivo"]},{"year":2021,"claim":"In zebrafish, showed PRPF31 loss arrests retinal progenitors in mitosis with DNA damage and preferential skipping of weak-5'-splice-site exons, with WT but not mutant human PRPF31 rescuing.","evidence":"prpf31 knockout zebrafish, transcriptome-wide splicing, cell-cycle/DNA-damage assays, human rescue","pmids":["33476374"],"confidence":"High","gaps":["Link between splicing changes and mitotic arrest not mechanistically closed","Relation to the direct kinetochore role not tested"]},{"year":2022,"claim":"Connected reduced PRPF31 dosage in patient RPE/organoids to tri-snRNP assembly defects, aggregation of mutant PRPF31 and ubiquitinated proteins, and autophagy-dependent survival.","evidence":"iPSC-derived RPE/organoids, proteomics, Cajal-body/speckle imaging, spliceosome assays, rapamycin treatment","pmids":["35297555"],"confidence":"Medium","gaps":["Direction of causality between aggregation and autophagy unresolved","Single lab"]},{"year":2022,"claim":"Reported a PRPF31–PRPH2 physical interaction in retinal cells, a candidate non-splicing link to photoreceptor structural proteins.","evidence":"Co-IP and immunofluorescence co-localization in HEK293T, ARPE-19, and mouse retina","pmids":["36088804"],"confidence":"Low","gaps":["Single Co-IP/co-localization without reciprocal or functional validation","Biological significance undefined"]},{"year":2023,"claim":"Proposed that the Usher protein SANS binds PRPF31 (and PRPF6) and that pathogenic SANS variants perturb these contacts, suggesting cross-talk between Usher and splicing machinery.","evidence":"FRET in cells, deep-learning structure prediction, and domain mapping","pmids":["38139438"],"confidence":"Low","gaps":["No reconstitution or experimental structure; relies on in silico prediction","Functional consequence for splicing not tested"]},{"year":2024,"claim":"Generalized the proliferation requirement beyond the retina, showing PRPF31 loss causes M-phase arrest and mis-splicing of mitotic genes in zebrafish hematopoietic progenitors.","evidence":"prpf31 knockout zebrafish, immunofluorescence, splicing transcriptomics, flow cytometry","pmids":["38382674"],"confidence":"Medium","gaps":["Tissue specificity of human disease still unexplained","Splicing-versus-kinetochore contribution not separated"]},{"year":2025,"claim":"Defined a PRPF31–FSCN2 axis for photoreceptor ciliogenesis, with FSCN2 overexpression partially rescuing cilia defects from PRPF31 loss.","evidence":"RNAi, RNA immunoprecipitation, FSCN2 rescue, and cilia quantification in 661W cells","pmids":["41265626"],"confidence":"Medium","gaps":["Whether the effect is via splicing or RNA binding not fully resolved","In vivo validation lacking"]},{"year":2026,"claim":"Identified a downstream stress cascade in which PRPF31 deficiency lowers PLK4, de-represses TFEB, hyperactivates autophagy, and produces mitochondrial dysfunction.","evidence":"Multi-model cell/animal study with localization, autophagy, mitochondrial, and reporter assays","pmids":["41932639"],"confidence":"Medium","gaps":["Link from splicing defect to PLK4 downregulation not defined","Causal ordering versus aggregation pathway unresolved"]},{"year":null,"claim":"Why a ubiquitously required spliceosomal and mitotic protein produces retina-restricted degeneration, and how its splicing-dependent and direct kinetochore functions are partitioned, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism explaining tissue specificity of RP11 despite ubiquitous expression","Splicing pool versus spindle/kinetochore pool of PRPF31 not biochemically separated","Causal hierarchy among mis-splicing, aggregation, autophagy, and mitochondrial defects undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,3,4,24]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,26]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003677","term_label":"DNA 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U4 SMALL NUCLEAR 2; RNU4-2","url":"https://www.omim.org/entry/620823"},{"mim_id":"617031","title":"PRE-mRNA-PROCESSING FACTOR 38A; PRPF38A","url":"https://www.omim.org/entry/617031"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRPF31"},"hgnc":{"alias_symbol":["NY-BR-99","PRP31","hPrp31","SNRNP61"],"prev_symbol":["RP11"]},"alphafold":{"accession":"Q8WWY3","domains":[{"cath_id":"1.10.246.90","chopping":"223-258_268-334","consensus_level":"medium","plddt":92.5699,"start":223,"end":334}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWY3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWY3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWY3-F1-predicted_aligned_error_v6.png","plddt_mean":77.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRPF31","jax_strain_url":"https://www.jax.org/strain/search?query=PRPF31"},"sequence":{"accession":"Q8WWY3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWY3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWY3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWY3"}},"corpus_meta":[{"pmid":"11545739","id":"PMC_11545739","title":"A 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Immunodepletion of 61K from HeLa nuclear extracts inhibits tri-snRNP formation; complementation with recombinant 61K restores all steps. 61K is operationally U4/U6 snRNP-specific but also interacts with the U5 snRNP-associated 102K protein (PRPF6), physically tethering U4/U6 to U5 to yield the tri-snRNP.\",\n      \"method\": \"Immunodepletion from HeLa nuclear extracts, recombinant protein complementation, two-hybrid analysis, biochemical co-sedimentation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with immunodepletion and complementation, plus two-hybrid and biochemical validation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"11867543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The conserved Nop domain of hPrp31 is a genuine RNP-binding module that recognizes a composite RNA-protein platform consisting of the 15.5K protein bound to U4 snRNA. The Nop domain exhibits both RNA and protein binding surfaces, and binding specificity is maintained despite relaxed RNA sequence requirements. Yeast two-hybrid analyses linked RP-causing mutations to an aberrant hPrp31–hPrp6 interaction that blocks U4/U6·U5 tri-snRNP formation.\",\n      \"method\": \"Crystal structure analysis of hPrp31–15.5K–U4 snRNA complex, biochemical binding assays, yeast two-hybrid\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation and mutagenesis; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"17412961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RNAi knockdown of hPrp31 (61K) in HeLa cells inhibits tri-snRNP formation in vivo, causing accumulation of stable U4/U6 di-snRNPs and U5 mono-snRNPs. In the absence of hPrp31, U4/U6 di-snRNPs and the recycling factor p110 accumulate in Cajal bodies, while U5 snRNPs remain in nucleoplasmic speckles, supporting a role for Cajal bodies in tri-snRNP recycling.\",\n      \"method\": \"RNAi in HeLa cells, biochemical fractionation, fluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with defined cellular and biochemical phenotype plus direct fluorescence localization; two orthogonal methods; replicated conceptually with parallel hPrp6 knockdown\",\n      \"pmids\": [\"15257298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hPrp31 binding to U4 snRNP requires the kink-turn structure (stem I and two-base-pair stem II) of the U4 5'-stem-loop pre-bound with 15.5K protein. Stem I could not be shortened and introduction of a third Watson-Crick base pair into stem II significantly reduced hPrp31 binding. The two-base-pair stem II of U4/U4atac snRNAs discriminates hPrp31 binding from NOP56/NOP58 binding to box C/D snoRNAs (which require a three-base-pair stem II).\",\n      \"method\": \"Hydroxyl radical footprinting, electrophoretic mobility shift assay (EMSA) with systematic U4 snRNA mutants, in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis and footprinting; single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"16857676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure analysis shows that the capping pentaloops of U4 and U4atac 5'-stem-loops adopt different conformations in ternary hPrp31–15.5K–snRNA complexes. In U4atac snRNA, a noncanonical base pair forms across the pentaloop enabling more intimate contacts with hPrp31; stacking of hPrp31-His270 on this base pair stabilizes the complex. Rational mutagenesis confirmed these interactions, explaining how hPrp31 achieves dual specificity for both U4 and U4atac snRNAs.\",\n      \"method\": \"Crystal structure analysis, gel-shift assays, rational mutagenesis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis and binding assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21784869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two RP11-linked missense mutations (A194E and A216P) in PRPF31 substantially hinder translocation of the protein into the nucleus when expressed in mammalian cells, as shown by western analysis and immunofluorescence. The A216P mutation introduced into yeast PRP31p only partially rescues growth at the restrictive temperature, indicating incomplete splicing function. No dominant-negative effect on splicing was detected in a human cell in vivo splicing assay.\",\n      \"method\": \"Yeast complementation assay, in vivo splicing assay in human cells, western blot, immunofluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (yeast complementation, human splicing assay, immunofluorescence) in single study; single lab\",\n      \"pmids\": [\"12444105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mutant PRPF31 proteins significantly inhibit pre-mRNA splicing of rhodopsin (RHO) intron 3 in retinal cells, as demonstrated by immunoprecipitation of PRPF31-containing splicing complexes that co-purify RHO transcripts. Expression of mutant PRPF31 in primary retinal cultures reduces rhodopsin expression and causes apoptosis of rhodopsin-positive retinal cells.\",\n      \"method\": \"Immunoprecipitation of splicing complexes, minigene splicing assay, primary retinal cell culture with mutant PRPF31 expression, immunofluorescence\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complexes plus functional splicing assay and primary cell apoptosis readout; single lab, multiple methods\",\n      \"pmids\": [\"15659613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Immunoprecipitation-coupled microarray analysis identified peripherin/RDS and FSCN2 transcripts as being associated with PRPF31-containing splicing complexes in retinal cells. Minigene assays demonstrated that mutant PRPF31 significantly inhibits pre-mRNA splicing of RDS and FSCN2, linking ubiquitous splicing factor dysfunction to photoreceptor-specific gene expression defects.\",\n      \"method\": \"Immunoprecipitation-coupled microarray (IP-chip), minigene splicing assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with follow-up functional minigene validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"17350276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Most PRPF31 mutations introducing premature termination codons result in null alleles through nonsense-mediated mRNA decay (NMD). Allele-specific measurement confirmed strong reduction of mutant transcripts; blocking NMD restored mutant mRNA but did not restore truncated protein synthesis even with proteasome inhibitors, indicating the pathogenic mechanism is haploinsufficiency rather than dominant-negative gain-of-function.\",\n      \"method\": \"Allele-specific RT-PCR, NMD inhibition, western blot, protein degradation pathway inhibitors\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal molecular methods (allele-specific qRT-PCR, NMD inhibition, western blot with proteasome inhibitors) across 9 patient cell lines; multiple PRPF31 mutations tested\",\n      \"pmids\": [\"18317597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRPF31 is imported into the nucleus via interaction with importin beta1, with no requirement for importin alpha1, as shown by GST pull-down assays. The disease-linked mutations A194E and A216P do not affect this importin beta1 interaction. FRAP of EGFP-tagged PRPF31 revealed a two-component nuclear entry process (fast tau ~6 s, slow tau ~80 s), unchanged by the mutations.\",\n      \"method\": \"GST pull-down with importin proteins, fluorescence recovery after photobleaching (FRAP) in live cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical pulldown plus live-cell FRAP; single lab, two orthogonal methods\",\n      \"pmids\": [\"16427773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The A216P (AD29) missense mutation in hPrp31 destabilizes the protein structure, leading to rapid degradation and significantly reduced association with U4 and U5 snRNPs in the cell nucleus. Overexpression of hPrp6 (a binding partner) reverses the effects of AD29 on cell proliferation and Cajal body structure. The mutation's pathology involves both insufficiency of functional hPrp31 and potential cytotoxicity from the unstable mutant.\",\n      \"method\": \"Co-immunoprecipitation with snRNPs, protein stability assays, cell proliferation assay, fluorescence microscopy of Cajal bodies, hPrp6 rescue overexpression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and cellular assays (Co-IP, stability, rescue by hPrp6); single lab\",\n      \"pmids\": [\"19293337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The A216P mutation in PRPF31 directly reduces splicing efficiency of RHO minigene intron 3 in an in vivo mammalian cell assay, and pull-down assays show that the mutant PRPF31 has a stronger interaction with PRPF6 than wild-type, suggesting a mechanism for splicing inhibition. Splicing of full-length RHO transcript is 100% efficient, indicating RP11 missense mutations act mainly through protein insufficiency/insolubility with a minor direct splicing effect.\",\n      \"method\": \"In vivo minigene splicing assay in transfected mammalian cells, GST pull-down assay between PRPF31 and PRPF6\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assay plus protein interaction pulldown; single lab, two orthogonal methods\",\n      \"pmids\": [\"18431455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTNNBL1, an armadillo-motif nuclear protein, interacts with PRPF31 through the nuclear localization sequence (NLS) of PRPF31. CTNNBL1 binds NLSs via its ARM domain, exhibiting selectivity distinct from karyopherin-alpha, suggesting a possible role in selective intranuclear targeting or interactions of splicing-associated complexes.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, identification of NLS-binding specificity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and pulldown; single lab but multiple binding assays demonstrating specific NLS-dependent interaction\",\n      \"pmids\": [\"21385873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNOT3, a subunit of the Ccr4-NOT transcription complex, acts as a transcriptional repressor of PRPF31. siRNA-mediated silencing of CNOT3 increases PRPF31 expression; chromatin immunoprecipitation showed CNOT3 directly binds the PRPF31 promoter. CNOT3 is the major modifier gene determining penetrance of PRPF31 mutations, and its variable expression correlates inversely with PRPF31 levels.\",\n      \"method\": \"siRNA knockdown of CNOT3, chromatin immunoprecipitation (ChIP), quantitative RT-PCR, western blot, next-generation sequencing of CNOT3 genomic region\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional siRNA rescue, and mRNA/protein correlation; multiple orthogonal methods; independent replication of PRPF31 expression-penetrance correlation\",\n      \"pmids\": [\"23144630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRP31 is ubiquitinated with K63-linked chains by the PRP19 complex and deubiquitinated by USP15 together with its substrate-targeting factor SART3. The USP15-SART3 complex also forms a ternary complex with USP4 to deubiquitinate PRP3. The ubiquitination/deubiquitination status of PRP31 regulates its interaction with U5 snRNP component PRP8, which is required for efficient splicing of chromosome-segregation genes, likely by stabilizing the U4/U6·U5 tri-snRNP complex.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin linkage analysis, siRNA knockdown, in vitro splicing assays, mass spectrometry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitin linkage typing, functional rescue assays, and splicing readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28088760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Prp31 and Sf3A2 directly bind spindle microtubules and the Ndc80 kinetochore complex in both Drosophila and human cells, with the Ndc80/HEC1-SF interaction restricted to M phase. Antibody injection into Drosophila embryos disrupts mitotic division within 1 minute, demonstrating a direct (non-splicing-mediated) role in chromosome segregation. In cells depleted of Prp31, the Ndc80 complex is not tightly associated with kinetochores.\",\n      \"method\": \"Anti-Prp31 antibody microinjection into Drosophila embryos, RNAi depletion in HeLa cells, co-immunoprecipitation with Ndc80 complex, microtubule binding assays, immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody injection with <1 min mitotic effect (rules out splicing mechanism), Co-IP with Ndc80, localization studies; multiple orthogonal methods in both fly and human cells\",\n      \"pmids\": [\"30475206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In PRPF31-mutated patient-derived retinal organoids and RPE cells, disrupted alternative splicing occurs for specific splicing programs including genes encoding pre-mRNA splicing proteins and genes implicated in ciliogenesis and cellular adhesion. RPE defects include disrupted apical-basal polarity, reduced trans-epithelial resistance, reduced phagocytic capacity, and decreased cilia length and incidence. In situ CRISPR/Cas9 correction of the pathogenic mutation rescued protein expression and key cellular phenotypes.\",\n      \"method\": \"Patient iPSC-derived retinal organoids and RPE, transcriptome profiling, Prpf31+/- mouse retina analysis, CRISPR/Cas9 correction with phenotypic rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptomics plus multiple cellular functional assays plus genetic rescue (CRISPR); corroborated in Prpf31+/- mouse model\",\n      \"pmids\": [\"30315276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mutant PRPF31 protein forms cytoplasmic aggregates in the RPE of a Prpf31-A216P mouse model, reducing nuclear protein levels. Wild-type PRPF31 is recruited into insoluble aggregates when mutant protein is overexpressed in vitro. In response to aggregation, Hspa4l (HSP70 family member) is overexpressed, which may facilitate correct folding and nuclear translocation of mutant protein.\",\n      \"method\": \"Mouse model analysis (Prpf31-A216P/+), immunofluorescence, protein solubility fractionation, in vitro overexpression, western blot\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus in vitro biochemistry showing aggregate recruitment and chaperone response; single lab\",\n      \"pmids\": [\"31892304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In prpf31 knockout zebrafish, retinal progenitor cell (RPC) differentiation and viability are severely disrupted at early embryonic stages. Mitotic arrest and DNA damage occur specifically in RPCs. Prpf31 deletion predominantly causes skipping of exons with weak 5' splice sites. Differentially spliced genes are enriched for DNA repair and mitotic progression functions. Wild-type human PRPF31 but not disease-associated mutants rescues the zebrafish phenotype.\",\n      \"method\": \"prpf31 knockout zebrafish, transcriptome-wide splicing analysis, cell cycle and DNA damage assays, human PRPF31 rescue expression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined cellular phenotype, transcriptome-wide splicing analysis, and genetically validated rescue with WT vs mutant human PRPF31\",\n      \"pmids\": [\"33476374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In PRPF31-mutated patient iPSC-derived RPE and retinal organoid cells, mutant PRPF31 is not incorporated into splicing complexes. Reduced PRPF31 wild-type levels cause tri-snRNP assembly defects in Cajal bodies, altered nuclear speckle morphology, and reduced active spliceosome formation. Progressive cytoplasmic aggregates containing mutant PRPF31 and ubiquitin-conjugated proteins accumulate. Activation of autophagy with rapamycin reduces cytoplasmic aggregates and improves cell survival.\",\n      \"method\": \"iPSC-derived RPE and retinal organoids, quantitative proteomics, immunofluorescence of Cajal bodies/nuclear speckles, spliceosome assembly assays, rapamycin treatment\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus cellular organelle analysis and pharmacological rescue; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"35297555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRPF31 reduction causes mis-splicing of phototransduction genes (RHO, ROM1, FSCN2, GNAT2, GNAT1) and RNA processing genes (PRPF3, PRPF8, PRPF4, PRPF19) in human organotypic retinal cultures. The splicing defects were identified by RNA-seq analysis of differential exon usage and intron retention after RNAi-mediated knockdown of PRPF31.\",\n      \"method\": \"RNAi knockdown in human organotypic retinal cultures, RNA-seq with differential exon usage and intron retention analysis\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with genome-wide splicing readout in tissue-relevant model; single lab\",\n      \"pmids\": [\"31654038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRPF31 is involved in HBV covalently closed circular DNA (cccDNA) production. PRPF31 knockdown by siRNA decreased cccDNA formation, and expression of siRNA-resistant PRPF31 rescued cccDNA formation. Chromatin immunoprecipitation and co-immunoprecipitation revealed association between PRPF31 and cccDNA, and co-overexpression of PRPF31 and HBx enhanced cccDNA formation.\",\n      \"method\": \"siRNA knockdown, rescue overexpression, chromatin immunoprecipitation, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with rescue, ChIP, and Co-IP; single lab, multiple methods but non-retinal function\",\n      \"pmids\": [\"27864147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRPF31 interacts with PRPH2 (peripherin-2) as shown by co-immunoprecipitation and co-localization in HEK293T, ARPE-19 cells, and mouse retina. PRPF31 could be pulled down with an anti-PRPH2 antibody.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and co-localization; single lab, limited functional follow-up\",\n      \"pmids\": [\"36088804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The USH1G protein SANS directly binds PRPF31 via two distinct conserved regions of its CENTn domain, as shown by FRET assays and in silico structural predictions. Pathogenic USH1G/SANS variants perturb binding to PRPF31 and PRPF6, and a conformational change in an intrinsically disordered region of SANS CENTn2 to a short alpha-helix is triggered by PRPF6 binding, suggesting sequential interactions.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) in cells, deep learning-based protein structure prediction, domain mapping\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — FRET in cells plus in silico predictions; no reconstitution or structural validation; single lab\",\n      \"pmids\": [\"38139438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRPF31 deficiency in 661W photoreceptor-like cells downregulates FSCN2 expression and reduces cilia number (as measured by IFT88 and ARL13B markers). RNA immunoprecipitation showed PRPF31-FSCN2 interaction. Overexpression of FSCN2 partially rescued the ciliary defects caused by PRPF31 knockdown, identifying a PRPF31–FSCN2 regulatory axis for photoreceptor ciliogenesis.\",\n      \"method\": \"RNAi knockdown, RNA immunoprecipitation (RIP), FSCN2 rescue overexpression, cilia quantification, RT-qPCR, western blot\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrating interaction, functional RNAi with rescue; single lab, multiple methods\",\n      \"pmids\": [\"41265626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRPF31 deficiency in zebrafish causes severe defects in hematopoietic stem and progenitor cell (HSPC) expansion. Prpf31-deficient HSPCs undergo malformed mitosis and M-phase arrest during expansion. Transcriptome analysis revealed extensive perturbation of alternative splicing of mitosis-related genes, mechanistically linking PRPF31 splicing function to HSPC proliferation.\",\n      \"method\": \"prpf31 knockout zebrafish, immunofluorescence, transcriptome/splicing analysis, flow cytometry of hematopoietic lineages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with cellular phenotype and transcriptome-wide splicing validation; single lab\",\n      \"pmids\": [\"38382674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast Prp31p (ortholog of human PRPF31) is essential for cell viability and required for pre-mRNA splicing both in vivo and in vitro, as shown by temperature-sensitive mutant analysis and direct splicing assays. The wild-type PRP31 gene was cloned by complementation; epitope-tagged Prp31p is functional in vivo.\",\n      \"method\": \"Temperature-sensitive mutant characterization, in vivo and in vitro splicing assays, gene cloning by complementation, western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro splicing assay plus in vivo complementation; foundational yeast study establishing essential splicing function\",\n      \"pmids\": [\"8604353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Fission yeast prp31+ is essential for vegetative growth and meiotic progression, and is synthetically lethal with prp6. Temperature-sensitive prp31-E1 cells display a pre-mRNA splicing defect at the restrictive temperature, confirming Prp31 as a general splicing factor required in both mitotic and meiotic contexts.\",\n      \"method\": \"Temperature-sensitive mutant, synthetic lethality with prp6, in vivo splicing analysis, gene cloning by complementation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (synthetic lethality with prp6) plus direct splicing assay; single study in fission yeast ortholog\",\n      \"pmids\": [\"10871341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRPF31 deficiency downregulates polo-like kinase 4 (PLK4), relieving its inhibition of transcription factor EB (TFEB). This triggers TFEB nuclear translocation and transcriptional upregulation of autophagy/lysosomal genes, driving autophagic hyperactivation. The resulting autophagic hyperactivation causes mitochondrial dysfunction (structural abnormalities, respiratory deficits, ATP deficiency, ROS accumulation), establishing a PLK4-TFEB-autophagy-mitochondria pathogenic axis.\",\n      \"method\": \"Multi-model approach (cell lines, animal models), protein localization, autophagy assays, mitochondrial function assays, transcriptional reporter assays\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-model mechanistic pathway dissection with functional readouts; single lab, newly published\",\n      \"pmids\": [\"41932639\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF31 encodes a ubiquitously expressed spliceosomal protein whose Nop domain binds a composite RNP platform (15.5K protein + U4/U4atac snRNA kink-turn) and also contacts PRPF6 (hPrp6/102K), physically tethering the U4/U6 di-snRNP to the U5 snRNP to form the U4/U6·U5 tri-snRNP required for each round of pre-mRNA splicing; K63-linked ubiquitination of PRPF31 by the PRP19 complex (reversed by USP15-SART3) regulates its interaction with PRPF8, controlling tri-snRNP dynamics; in the absence of PRPF31, U4/U6 di-snRNPs accumulate in Cajal bodies implicating these organelles in tri-snRNP recycling; PRPF31 additionally binds spindle microtubules and the Ndc80 kinetochore complex to directly support chromosome segregation independently of splicing; and in photoreceptors/RPE, haploinsufficiency caused by NMD-mediated destruction of mutant alleles leads to mis-splicing of phototransduction and ciliogenesis genes, RPE ciliary defects, progressive cytoplasmic protein aggregation, and a PLK4-TFEB-autophagy-mitochondria stress cascade, collectively causing the retina-restricted degeneration of RP11.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRPF31 is an essential pre-mRNA splicing factor that drives assembly of the U4/U6·U5 tri-snRNP required for each round of splicing [#0, #26]. Its conserved Nop domain recognizes a composite RNP platform—the 15.5K protein bound to the kink-turn of the U4 (and U4atac) snRNA 5'-stem-loop—and the geometry of a two-base-pair stem II discriminates this binding from box C/D snoRNP proteins, allowing PRPF31 to engage both U4 and U4atac snRNAs [#1, #3, #4]. By simultaneously contacting this U4/U6-associated platform and the U5 snRNP protein PRPF6, PRPF31 physically tethers the U4/U6 di-snRNP to U5 to generate the tri-snRNP; loss of PRPF31 blocks tri-snRNP formation and causes U4/U6 di-snRNPs and the recycling factor p110 to accumulate in Cajal bodies, implicating these bodies in tri-snRNP recycling [#0, #2]. K63-linked ubiquitination of PRPF31 by the PRP19 complex, reversed by USP15-SART3, modulates its interaction with PRPF8 and thereby tunes tri-snRNP dynamics and splicing of chromosome-segregation genes [#14]. Beyond splicing, PRPF31 directly binds spindle microtubules and the Ndc80 kinetochore complex during M phase to support chromosome segregation, a function independent of its splicing role [#15]; consistent with this, PRPF31 loss causes mitotic arrest and DNA damage in proliferating progenitor populations [#18, #25]. Mutations in PRPF31 cause autosomal dominant retinitis pigmentosa (RP11) through haploinsufficiency: premature-termination alleles are eliminated by nonsense-mediated decay and missense alleles such as A216P destabilize and mislocalize the protein, with disease penetrance set by the transcriptional repressor CNOT3 acting on the PRPF31 promoter [#8, #10, #13]. Reduced PRPF31 dosage produces retina-specific pathology—mis-splicing of phototransduction and ciliogenesis genes, RPE ciliary and polarity defects, cytoplasmic protein aggregation, and a PLK4-TFEB-autophagy-mitochondria stress cascade [#16, #20, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the PRPF31 ortholog is an essential, conserved general splicing factor, setting the functional baseline for the human protein.\",\n      \"evidence\": \"Temperature-sensitive mutants and in vivo/in vitro splicing assays in budding yeast Prp31p, with cloning by complementation\",\n      \"pmids\": [\"8604353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the snRNP step at which Prp31p acts\", \"Human protein not yet characterized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic epistasis showed Prp31 functions together with Prp6, foreshadowing the di-snRNP–U5 bridging role.\",\n      \"evidence\": \"Temperature-sensitive prp31 mutant and synthetic lethality with prp6 in fission yeast, plus splicing analysis\",\n      \"pmids\": [\"10871341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of the Prp31–Prp6 functional interaction not defined\", \"Did not test the human orthologs directly\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the specific molecular step PRPF31 controls—tri-snRNP formation—by showing depletion blocks assembly and recombinant protein restores it, and identified PRPF6 as its U5 contact.\",\n      \"evidence\": \"Immunodepletion/complementation of HeLa nuclear extracts, two-hybrid, and co-sedimentation\",\n      \"pmids\": [\"11867543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RNP and PRPF6 binding not yet resolved\", \"In vivo consequence of loss not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First connected RP-causing missense mutations to a cellular defect, showing impaired nuclear import and incomplete splicing function without dominant-negative splicing inhibition.\",\n      \"evidence\": \"Yeast complementation, human in vivo splicing assay, immunofluorescence and western blot of A194E/A216P\",\n      \"pmids\": [\"12444105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether pathology is haploinsufficiency or toxicity\", \"Import defect mechanism unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in vivo that PRPF31 loss arrests tri-snRNP assembly and traps U4/U6 di-snRNPs in Cajal bodies, implicating these bodies in tri-snRNP recycling.\",\n      \"evidence\": \"RNAi in HeLa cells with biochemical fractionation and fluorescence microscopy\",\n      \"pmids\": [\"15257298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how Cajal-body localization couples to recycling\", \"Recovery kinetics of the tri-snRNP not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the RNA determinant of PRPF31 binding—the U4 kink-turn with a two-base-pair stem II—explaining specificity against snoRNP proteins.\",\n      \"evidence\": \"Hydroxyl-radical footprinting and EMSA with systematic U4 snRNA mutants\",\n      \"pmids\": [\"16857676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic contacts (later by crystallography)\", \"Protein-binding surface not mapped here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified importin beta1 as the nuclear-import receptor for PRPF31 and showed RP mutations do not impair this interaction, narrowing the basis of mutant mislocalization.\",\n      \"evidence\": \"GST pull-down with importins and FRAP of EGFP-PRPF31 in live cells\",\n      \"pmids\": [\"16427773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier reported import defect of mutants unresolved\", \"Two-component entry kinetics not mechanistically explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the structural mechanism: the Nop domain is a bona fide RNP-binding module recognizing the 15.5K–U4 platform, and RP mutations act by perturbing the PRPF31–PRPF6 interaction that builds the tri-snRNP.\",\n      \"evidence\": \"Crystal structure of hPrp31–15.5K–U4 snRNA with binding assays and yeast two-hybrid\",\n      \"pmids\": [\"17412961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full tri-snRNP assembly intermediate\", \"Functional consequence in retina not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked PRPF31 dysfunction to photoreceptor biology by showing mutant protein impairs splicing of retinal transcripts and triggers apoptosis of rhodopsin-positive cells.\",\n      \"evidence\": \"Immunoprecipitation of splicing complexes, minigene assays, and primary retinal cultures with mutant PRPF31\",\n      \"pmids\": [\"15659613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate direct splicing inhibition from protein insufficiency\", \"Mechanism of retina specificity unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended the retinal target set, identifying RDS/peripherin and FSCN2 transcripts whose splicing is sensitive to mutant PRPF31.\",\n      \"evidence\": \"IP-coupled microarray and minigene splicing assays in retinal cells\",\n      \"pmids\": [\"17350276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding versus complex co-purification not distinguished\", \"Quantitative dosage dependence not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the disease mechanism as haploinsufficiency by showing PTC alleles are degraded by NMD with no rescued truncated protein, excluding dominant-negative gain-of-function.\",\n      \"evidence\": \"Allele-specific RT-PCR, NMD and proteasome inhibition, western blot across patient cell lines\",\n      \"pmids\": [\"18317597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain why only the retina degenerates\", \"Missense alleles handled in separate studies\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the A216P missense allele destabilizes the protein, reduces snRNP association, and is rescued by excess PRPF6, supporting an insufficiency mechanism for missense mutations.\",\n      \"evidence\": \"Co-IP with snRNPs, stability and proliferation assays, Cajal-body imaging, hPrp6 overexpression rescue\",\n      \"pmids\": [\"19293337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of insufficiency versus mutant cytotoxicity not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that A216P paradoxically binds PRPF6 more tightly while reducing minigene splicing, refining the view that RP11 missense mutations act mainly through insufficiency/insolubility.\",\n      \"evidence\": \"In vivo minigene splicing assay and GST pull-down between PRPF31 and PRPF6\",\n      \"pmids\": [\"18431455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stronger PRPF6 binding not mechanistically reconciled with reduced function\", \"Effect on full tri-snRNP not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the dual snRNA specificity by showing distinct pentaloop conformations of U4 versus U4atac and a His270 stacking contact stabilizing the complex.\",\n      \"evidence\": \"Crystal structures of ternary hPrp31–15.5K–snRNA complexes with gel-shift and rational mutagenesis\",\n      \"pmids\": [\"21784869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for minor-spliceosome splicing not tested in cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified CTNNBL1 as an NLS-binding partner with selectivity distinct from karyopherin-alpha, hinting at a dedicated intranuclear targeting route.\",\n      \"evidence\": \"Co-IP and pulldown mapping NLS-dependent binding\",\n      \"pmids\": [\"21385873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the interaction not established\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Explained variable penetrance of PRPF31 mutations by identifying CNOT3 as a direct transcriptional repressor whose expression sets residual wild-type PRPF31 dosage.\",\n      \"evidence\": \"siRNA knockdown, ChIP at the PRPF31 promoter, qRT-PCR/western, and sequencing of CNOT3\",\n      \"pmids\": [\"23144630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trans/cis variants controlling CNOT3 levels in patients\", \"Tissue-specific regulation not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated PRPF31 in HBV cccDNA formation, indicating a function beyond the spliceosome.\",\n      \"evidence\": \"siRNA knockdown with rescue, ChIP, and Co-IP linking PRPF31 to cccDNA and HBx\",\n      \"pmids\": [\"27864147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect role in cccDNA biogenesis not resolved\", \"No structural basis for cccDNA association\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a regulatory layer: K63-ubiquitination of PRPF31 by the PRP19 complex, reversed by USP15-SART3, controls PRPF31–PRPF8 interaction and splicing of chromosome-segregation genes.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitin-linkage typing, siRNA, in vitro splicing, and mass spectrometry\",\n      \"pmids\": [\"28088760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site(s) on PRPF31 not mapped\", \"How modification status is signaled remains unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a splicing-independent, direct mitotic function: PRPF31 binds spindle microtubules and the Ndc80 complex during M phase, with rapid antibody-injection effects ruling out a splicing mechanism.\",\n      \"evidence\": \"Antibody microinjection in Drosophila embryos, HeLa RNAi, Co-IP with Ndc80, microtubule-binding and imaging\",\n      \"pmids\": [\"30475206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of microtubule/Ndc80 binding unresolved\", \"Relationship to splicing pool of PRPF31 not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Modeled RP11 in human retinal organoids/RPE, showing disrupted splicing of splicing and ciliogenesis genes plus RPE polarity, barrier, phagocytosis, and ciliary defects, with CRISPR correction rescuing phenotypes.\",\n      \"evidence\": \"Patient iPSC-derived retinal organoids and RPE, transcriptomics, Prpf31+/- mouse retina, CRISPR/Cas9 correction\",\n      \"pmids\": [\"30315276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal chain from mis-splicing to ciliary defect not fully traced\", \"Retina-restriction still unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the retinal mis-splicing program upon PRPF31 reduction, including phototransduction and RNA-processing genes.\",\n      \"evidence\": \"RNAi in human organotypic retinal cultures with RNA-seq for differential exon usage and intron retention\",\n      \"pmids\": [\"31654038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which mis-spliced events are causal for degeneration not isolated\", \"Single model system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified protein aggregation as a downstream consequence, showing mutant PRPF31 forms cytoplasmic aggregates that sequester wild-type protein and induce an HSP70 chaperone response.\",\n      \"evidence\": \"Prpf31-A216P mouse RPE, solubility fractionation, in vitro overexpression, and western blot\",\n      \"pmids\": [\"31892304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether aggregation is cause or consequence of degeneration unclear\", \"Hspa4l rescue not functionally tested in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In zebrafish, showed PRPF31 loss arrests retinal progenitors in mitosis with DNA damage and preferential skipping of weak-5'-splice-site exons, with WT but not mutant human PRPF31 rescuing.\",\n      \"evidence\": \"prpf31 knockout zebrafish, transcriptome-wide splicing, cell-cycle/DNA-damage assays, human rescue\",\n      \"pmids\": [\"33476374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between splicing changes and mitotic arrest not mechanistically closed\", \"Relation to the direct kinetochore role not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected reduced PRPF31 dosage in patient RPE/organoids to tri-snRNP assembly defects, aggregation of mutant PRPF31 and ubiquitinated proteins, and autophagy-dependent survival.\",\n      \"evidence\": \"iPSC-derived RPE/organoids, proteomics, Cajal-body/speckle imaging, spliceosome assays, rapamycin treatment\",\n      \"pmids\": [\"35297555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of causality between aggregation and autophagy unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported a PRPF31–PRPH2 physical interaction in retinal cells, a candidate non-splicing link to photoreceptor structural proteins.\",\n      \"evidence\": \"Co-IP and immunofluorescence co-localization in HEK293T, ARPE-19, and mouse retina\",\n      \"pmids\": [\"36088804\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/co-localization without reciprocal or functional validation\", \"Biological significance undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed that the Usher protein SANS binds PRPF31 (and PRPF6) and that pathogenic SANS variants perturb these contacts, suggesting cross-talk between Usher and splicing machinery.\",\n      \"evidence\": \"FRET in cells, deep-learning structure prediction, and domain mapping\",\n      \"pmids\": [\"38139438\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution or experimental structure; relies on in silico prediction\", \"Functional consequence for splicing not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized the proliferation requirement beyond the retina, showing PRPF31 loss causes M-phase arrest and mis-splicing of mitotic genes in zebrafish hematopoietic progenitors.\",\n      \"evidence\": \"prpf31 knockout zebrafish, immunofluorescence, splicing transcriptomics, flow cytometry\",\n      \"pmids\": [\"38382674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue specificity of human disease still unexplained\", \"Splicing-versus-kinetochore contribution not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a PRPF31–FSCN2 axis for photoreceptor ciliogenesis, with FSCN2 overexpression partially rescuing cilia defects from PRPF31 loss.\",\n      \"evidence\": \"RNAi, RNA immunoprecipitation, FSCN2 rescue, and cilia quantification in 661W cells\",\n      \"pmids\": [\"41265626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is via splicing or RNA binding not fully resolved\", \"In vivo validation lacking\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a downstream stress cascade in which PRPF31 deficiency lowers PLK4, de-represses TFEB, hyperactivates autophagy, and produces mitochondrial dysfunction.\",\n      \"evidence\": \"Multi-model cell/animal study with localization, autophagy, mitochondrial, and reporter assays\",\n      \"pmids\": [\"41932639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link from splicing defect to PLK4 downregulation not defined\", \"Causal ordering versus aggregation pathway unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Why a ubiquitously required spliceosomal and mitotic protein produces retina-restricted degeneration, and how its splicing-dependent and direct kinetochore functions are partitioned, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism explaining tissue specificity of RP11 despite ubiquitous expression\", \"Splicing pool versus spindle/kinetochore pool of PRPF31 not biochemically separated\", \"Causal hierarchy among mis-splicing, aggregation, autophagy, and mitochondrial defects undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 3, 4, 24]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 26]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9, 12]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 14, 26]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 15, 18, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19, 28]}\n    ],\n    \"complexes\": [\n      \"U4/U6·U5 tri-snRNP\",\n      \"U4/U6 di-snRNP\",\n      \"Ndc80 kinetochore complex\"\n    ],\n    \"partners\": [\n      \"PRPF6\",\n      \"PRPF8\",\n      \"SNU13\",\n      \"PRPF19\",\n      \"USP15\",\n      \"SART3\",\n      \"CTNNBL1\",\n      \"NDC80\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}